? A role for green tea in the prevention of human prostate cancer is supported by both epidemiological studies and laboratory investigations. Green tea extract (GTP) contains a number of bioactive polyphenolic compounds that account for its anti-carcinogenic properties. Previous studies have shown that oral infusion of GTP dramatically reduces tumor burden and metastasis in a spontaneous autochthonous transgenic mouse model of prostate cancer known as TRAMP. These data support the use of the TRAMP model to examine the molecular mechanisms involved in GTP-mediated prostate cancer chemoprevention. Recently, green tea polyphenols were identified as potent inhibitors of DNA methylation, a critical oncogenic mechanism. This suggests a novel and direct mechanism to account for the chemopreventive properties of GTP. Based on these data, it is hypothesized that DNA methylation changes are involved in the etiology of TRAMP prostate cancer, and that the chemopreventive effect of GTP in TRAMP is due to its ability to prevent or reverse aberrant DNA hypermethylation. To test this hypothesis, this proposal will: 1) Define the epigenetic changes coincident with prostate cancer progression in the TRAMP model; and 2) Determine the effect of GTP treatment on epigenetic parameters in TRAMP mice. Because prostate cancer has a long latency period and is most prevalent in men over the age of 65, dietary interventions that modestly delay progression time would have a profound impact on prostate cancer death rates. In this regard, GTP has the potential for significant utility as a chemopreventive agent in prostate cancer patients. Understanding the molecular mechanism(s) responsible for the activity of GTP is essential for the optimal design of prostate cancer chemoprevention trials and for the identification of novel molecular biomarkers to follow in clinical studies of GTP. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA128062-02
Application #
7295730
Study Section
Special Emphasis Panel (ZES1-LWJ-E (EP))
Program Officer
Ross, Sharon A
Project Start
2006-09-15
Project End
2009-08-31
Budget Start
2007-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2007
Total Cost
$145,523
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Karpf, Adam R; Bai, Suxia; James, Smitha R et al. (2009) Increased expression of androgen receptor coregulator MAGE-11 in prostate cancer by DNA hypomethylation and cyclic AMP. Mol Cancer Res 7:523-35
Mavis, Cory K; Morey Kinney, Shannon R; Foster, Barbara A et al. (2009) Expression level and DNA methylation status of glutathione-S-transferase genes in normal murine prostate and TRAMP tumors. Prostate 69:1312-24
Morey Kinney, Shannon R; Zhang, Wa; Pascual, Marien et al. (2009) Lack of evidence for green tea polyphenols as DNA methylation inhibitors in murine prostate. Cancer Prev Res (Phila) 2:1065-75
Camoriano, Marta; Kinney, Shannon R Morey; Moser, Michael T et al. (2008) Phenotype-specific CpG island methylation events in a murine model of prostate cancer. Cancer Res 68:4173-82
Morey Kinney, Shannon R; Smiraglia, Dominic J; James, Smitha R et al. (2008) Stage-specific alterations of DNA methyltransferase expression, DNA hypermethylation, and DNA hypomethylation during prostate cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol Cancer Res 6:1365-74
Karpf, Adam R (2007) Epigenomic reactivation screening to identify genes silenced by DNA hypermethylation in human cancer. Curr Opin Mol Ther 9:231-41